Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy
Majida Charif, Arnaud Chevrollier, Naïg Guéguen, Céline Bris, David Goudenège, Valérie Desquiret‐Dumas, Stéphanie Leruez, Estelle Colin, Audrey Meunier, Catherine Vignal, Vasily Smirnov, Sabine Defoort‐Dhellemmes, Isabelle Drumare Bouvet, Cyril Goizet, Marcela Votruba, Neringa Jurkutė, Patrick Yu‐Wai‐Man, Francesca Tagliavini, Leonardo Caporali, Chiara La Morgia, Valério Carelli, Vincent Procaccio, Xavier Zanlonghi, Isabelle Meunier, Pascal Reynier, Dominique Bonneau, Patrizia Amati‐Bonneau, Guy Lenaers
Abstract
<h3>Objective</h3> To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. <h3>Methods</h3> Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. <h3>Results</h3> We identified 7 and 8 new heterozygous pathogenic variants in <i>SPG7</i> and <i>AFG3L2</i>. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in <i>AFG3L2</i> that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the <i>SPG7</i> variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported. <h3>Conclusions</h3> Our results position <i>SPG7</i> and <i>AFG3L2</i> as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.